1. Field of the Invention
The present invention relates to the use of two novel compounds as reference standards for determining the purity or stability of amlodipine maleate substances and pharmaceutical compositions.
2. Description of the Related Arts
Pharmaceutical products are regulated in most countries by a government agency. For example, the U.S. Food and Drug Administration (FDA) generally requires an applicant to show safety and efficacy of the pharmaceutical product during the approval/review phase and continues to monitor the safety of the drug post-approval. Similar requirements exist in many European countries and elsewhere in the world. In order to satisfy safety concerns, the regulatory agencies generally require a manufacturing specification that sets the maximum amount of each identified impurity as well as the maximum amount for all remaining unidentified impurities. Once approved, each batch or lot of the pharmaceutical product is tested to insure that the specification is met. Further, stability testing is performed on the pharmaceutical product in order to show that the composition does not substantially or materially change over time; i.e. over its indicated shelf-life. It is important that before its administration to a patient that the pharmaceutical product does not deviate from its approved specification in a way that might detract from its safety or efficacy. Good practice warrants keeping a sample from every commercial batch released to the public so that the stability can be monitored and any defect uncovered and corrected.
Accordingly, pharmaceuticals are tested for purity both during manufacture and subsequently during its shelf-life. Typically, the product is tested by comparing certain analytical results with those of a standard reference result. For impurity detection, this normally means assaying the pharmaceutical product and comparing the result to the result obtained for a substantially pure form of the suspected impurity in the same assay. Sources of potential impurities in a pharmaceutically active agent or formulation include:
residual amounts of synthetic precursors
side product arisen from the synthesis and elaboration of the active substance
residual solvents
degradation products appearing during storage including products resulted form interactions with excipients in formulations
isomers of the active agent
trace contaminants e.g. from equipment and environment.
Without identification of the potential impurity and a synthetic route to make a reference standard therefore, it is difficult or impossible to efficiently assay for the impurity or to otherwise monitor its level in the pharmaceutical product.
Amlodipine besylate is a highly successful pharmaceutical sold by Pfizer under the tradename NORVASC for treating hypertension and angina. Amlodipine itself was first patented in EP 089 167 and corresponding U.S. Pat. No. 4,572,909. These patents identify that one of the most preferred compounds is 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine. This compound, which is now commonly known as amlodipine, has the following formula: 
Examples 8, 11, 12, and 22 of EP 089 167 show the synthesis of amlodipine in the maleate salt form. While a variety of acid addition salts are generically taught to be suitable, the maleate salt is identified as the most preferred acid addition salt. However, subsequently EP 244 944 and corresponding U.S. Pat. No. 4,879,303 were issued directed to the besylate (or benzene sulfonate) salt of amlodipine. The besylate salt is stated to provide certain advantages over the known salts including good formulating properties. The quality standards for amlodipine besylate is provided in Pharmeuropa 10(2),187 (1998).
Indeed, a review of the available portions of the NORVASC (amlodipine besylate) New Drug Application (NDA) filed with the U.S. Food and Drug Administration by Pfizer reveals that a switch was made during development from the original maleate salt to the later besylate salt. (See xe2x80x9cReview of Original NDAxe2x80x9d for NDA# 19-787 of 10.10.1990, obtainable from FDA under Freedom of Information Act). The reasons for the switch were apparently tableting and stability problems. However, the precise stability and tableting problems/issues/causes are not publicly disclosed in the information available from the FDA.
Amlodipine maleate is, however, still a useful salt of amlodipine. It would be desirable to identify and solve the stability problems associated therewith and to provide a method for monitoring its production.
The present invention relates to the discovery of two novel impurities associated with amlodipine maleate substances and its pharmaceutical compositions. One aspect of the present invention relates to a process which comprises assaying a substantially pure amlodipine aspartate or amlodipine maleamide under a set of conditions to obtain a reference standard analytical result for said set of conditions. A further aspect of the invention relates to a process of testing purity or stability of a sample of amlodipine maleate or a pharmaceutical dosage form comprising amlodipine maleate which comprises assaying a sample of an amlodipine maleate substance or composition for the presence of amlodipine aspartate or amlodipine maleamide. For example, a process for checking the purity or stability of an amlodipine maleate substance or composition that comprises assaying an amlodipine maleate substance or composition to obtain an analytical result; and comparing the analytical result to a corresponding reference standard analytical result for amlodipine aspartate or amlodipine maleamide to determine if the purity or stability of the amlodipine maleate substance or composition is satisfactory. Another aspect of the invention relates to a process for producing pharmaceutically suitable amlodipine maleate solid dosage forms. The process comprises blending amlodipine maleate with at least one pharmaceutically acceptable excipient to form a blend; either (a) filling the blend into capsules or (b) compressing the blend in to tablets, to form a production lot of amlodipine maleate pharmaceutical solid dosage forms; removing a sample of said amlodipine maleate pharmaceutical solid dosage forms from the production lot; subjecting the sample to an assay to obtain a sample analytical result; comparing the sample analytical result to a corresponding reference standard analytical result for amlodipine aspartate or amlodipine maleamide to determine the amount of amlodipine aspartate or amlodipine maleamide relative to said amlodipine maleate; and selling or releasing the production lot if the relative amount of amlodipine aspartate or amlodipine maleamide is not greater than the pre-determined/approved limit, e.g. 1.0 wt %, preferably 0.1 wt % based on the amount of amlodipine maleate.